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Massi D.,University of Florence | Simi L.,University of Florence | Sensi E.,Laboratory of Molecular Pathology | Baroni G.,University of Florence | And 8 more authors.
Modern Pathology | Year: 2015

Testing for NRAS is now integral part in the assessment of metastatic melanoma patients because there is evidence that NRAS-mutated patients may be sensitive to MEK inhibitors, and RAS mutation is a common mechanism of acquired resistance during treatment with BRAF inhibitors. This study evaluated the sensitivity and specificity of immunohistochemical analysis using an N-Ras (Q61R) antibody to detect the presence of the NRASQ61R mutation in melanoma patients. A total of 98 primary cutaneous melanomas that have undergone examination of NRAS mutation were retrieved from a multicentric database. Formalin-fixed and paraffin-embedded melanoma tissues were analyzed for BRAF and NRAS mutations by independent, blinded observers using both conventional DNA molecular techniques and immunohistochemistry with the novel anti-human N-Ras (Q61R) monoclonal antibody (clone SP174). The antibody showed a sensitivity of 100% (14/14) and a specificity of 100% (83/83) for detecting the presence of an NRASQ61R mutation. Of the NRAS-mutated cases, none of the non-Q61R cases stained positive with the antibody (0/7). There were three cases with discordant NRAS mutational results. Additional molecular analysis confirmed the immunohistochemically obtained NRAS result in all cases, suggesting that a multiple analytical approach can be required to reach the correct sample classification. The reported immunohistochemical method is an accurate, rapid, and cost-effective method for detecting NRASQ61R mutation in melanoma patients, and represents a valuable supplement to traditional mutation testing. If validated in further studies, genetic testing would only be required for immunohistochemistry-negative patients to detect non-Q61R mutations.


Caldarella A.,Institute for Study and Cancer Prevention ISPO | Buzzoni C.,Institute for Study and Cancer Prevention ISPO | Crocetti E.,Institute for Study and Cancer Prevention ISPO | Bianchi S.,University of Florence | And 7 more authors.
Journal of Cancer Research and Clinical Oncology | Year: 2013

Introduction: The special types of breast cancer seem to have not only distinct morphological features but also distinct biological features. Materials and methods: Women diagnosed with a first primary invasive breast cancer in the 2004-2005 period were identified through Tuscan Cancer Registry. Information on age, tumor size, lymph node status, histological type and grade, hormonal receptors, HER2 immunohistochemical expression were collected. Five subtypes were defined: luminal A, luminal B HER2+, luminal B HER2-, triple negative, and HER2 positive. The association between the histological type and molecular subgroups was assessed by a Fisher's exact test, and a multinomial logistic regression model was used. Results: Out of 1,487 patients, 34 % were luminal A subtype, 25 % luminal B HER2-, 11 % luminal B HER2+, 19 % triple negative, and 10.2 % HER2+; 58.5 % of cancers were ductal NOS types. With luminal A as reference, histological types distribution was significantly different between the subgroups. Mucinous, tubular, and cribriform histotypes were found among luminal A cancers more than in other subgroups; all medullary carcinomas were triple negative cancers. Pathological stage at diagnosis was more advanced, and histological grade was lower among subgroups other than luminal A. Conclusions: Significant association between breast cancer histotypes and molecular subgroups was found. © 2012 Springer-Verlag Berlin Heidelberg.


Caldarella A.,Institute for Study and Cancer Prevention ISPO | Puliti D.,Institute for Study and Cancer Prevention ISPO | Crocetti E.,Institute for Study and Cancer Prevention ISPO | Bianchi S.,University of Florence | And 7 more authors.
Journal of Cancer Research and Clinical Oncology | Year: 2013

Introduction: In a population-based screening program, a percentage of tumors remain undetected; these tumors comprise a heterogeneous group, and they are more likely to have adverse prognostic features. The aim of this study was to identify differences in biological characteristics of screen-detected versus interval breast cancers in a population-based screening program according to molecular subtypes. Materials and methods: We analyzed the population-based data from a long-running screening program in the area of Florence. Data on screening history and on age, T and N status, grade, histotype, hormonal status and Ki-67 and HER2 expression were retrieved. Subtypes of breast cancer were defined on the expression of ER, PR, Ki-67 and HER2: luminal A if ER/PR+, HER2- and Ki67 <14 %, luminal B (HER2 negative) if ER/PR+, HER2- and Ki67 ≥14 %, luminal B (HER2 positive) if ER/PR+ and HER2+, triple negative if ER/PR-and HER2-, HER2 positive if ER/PR- and HER2+. Association between molecular subtypes and mode of detection will be evaluated by a logistic regression model adjusted for the potential confounding variables. Results: Information about biomarkers was known for 277 cases, 211 screening-detected and 66 interval cancers. Among interval cases, the triple-negative cancers were more represented than luminal A (OR = 3.52; CI, 1.112-11.13; p = 0.0319), while the proportion of HER2+ was quite similar (OR = 1.57; p = 0.4709). Conclusion: Although made on a small number of cases, our results suggest a difference in distribution of molecular subtypes according to mode detection, confirming the results of earlier studies. © 2012 Springer-Verlag.


PubMed | Friedrich Miescher Institute for Biomedical Research, Laboratory of Molecular Pathology, SM Annunziata Hospital, Papa Giovanni XXIII Hospital and 2 more.
Type: Journal Article | Journal: Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc | Year: 2015

Testing for NRAS is now integral part in the assessment of metastatic melanoma patients because there is evidence that NRAS-mutated patients may be sensitive to MEK inhibitors, and RAS mutation is a common mechanism of acquired resistance during treatment with BRAF inhibitors. This study evaluated the sensitivity and specificity of immunohistochemical analysis using an N-Ras (Q61R) antibody to detect the presence of the NRASQ61R mutation in melanoma patients. A total of 98 primary cutaneous melanomas that have undergone examination of NRAS mutation were retrieved from a multicentric database. Formalin-fixed and paraffin-embedded melanoma tissues were analyzed for BRAF and NRAS mutations by independent, blinded observers using both conventional DNA molecular techniques and immunohistochemistry with the novel anti-human N-Ras (Q61R) monoclonal antibody (clone SP174). The antibody showed a sensitivity of 100% (14/14) and a specificity of 100% (83/83) for detecting the presence of an NRASQ61R mutation. Of the NRAS-mutated cases, none of the non-Q61R cases stained positive with the antibody (0/7). There were three cases with discordant NRAS mutational results. Additional molecular analysis confirmed the immunohistochemically obtained NRAS result in all cases, suggesting that a multiple analytical approach can be required to reach the correct sample classification. The reported immunohistochemical method is an accurate, rapid, and cost-effective method for detecting NRASQ61R mutation in melanoma patients, and represents a valuable supplement to traditional mutation testing. If validated in further studies, genetic testing would only be required for immunohistochemistry-negative patients to detect non-Q61R mutations.


Chiarugi A.,Institute for Study and Cancer Prevention ISPO | Nardini P.,Institute for Study and Cancer Prevention ISPO | Crocetti E.,Institute for Study and Cancer Prevention ISPO | Carli P.,University of Florence | And 6 more authors.
Journal of the European Academy of Dermatology and Venereology | Year: 2012

Background Having a familial member affected by cutaneous melanoma is a risk factor for this neoplasm. Only a few epidemiological case-control studies have been carried out to investigate whether familial and sporadic melanomas show different clinical and histopathological features. Objective The aim of this study was to evaluate eventual different features and risk factors in subjects affected by familial and sporadic cutaneous melanoma. Methods A case-control multicentre study interesting 1407 familial (n = 92) and sporadic (n = 1315) melanomas in the Italian population. The analysis was made using t-test for continuous variables and chi-squared test for categorized ones. The variables which have shown statistically significant differences in the two groups in the univariate analysis were included in a multivariate model. Results The results showed some main significantly clinical differences between the two groups investigated: earlier age at diagnosis, a greater proportion of sunburns and a higher number of naevi were observed for the familial cases compared with sporadic ones. Nevertheless, we did not find a diagnostic anticipation in familial melanomas, in fact the invasion level and the thickness of melanomas was similar in the two groups. Conclusion Some relevant clinical differences are observed between the two groups examined. The familial melanoma members, although carriers of constitutional risk factors, are not careful enough to primary and secondary prevention. © 2011 European Academy of Dermatology and Venereology.


Caldarella A.,Institute for Study and Cancer Prevention ISPO | Crocetti E.,Institute for Study and Cancer Prevention ISPO | Messerini L.,University of Florence | Paci E.,Institute for Study and Cancer Prevention ISPO
International Journal of Colorectal Disease | Year: 2013

Background: Conflicting results on the shift of right-left ratio in colon cancer incidence have been reported. We examine incidence trends by subsite in a population-based study. Materials and methods: Colorectal cancer cases diagnosed in the 1985-2005 period were identified through the Tuscany Cancer Registry. Colon subsite was defined as proximal and distal; gender, age at diagnosis, histology, and stage were analyzed. Average annual incidence and age-specific rates according to subsite were calculated. Results: A total of 21,160 colorectal cancer cases were extracted; in 18,311 cases, the subsite was identified: 6,916 rectal, 5,239 proximal, and 6,156 distal. A larger proportion of distal colon cancers presented as early stage when compared with proximal. Incidence of rectal and distal colon cancer remained stable, while proximal colon cancer incidence increased. Conclusions: Proximal colon cancer incidence rate increased through the period. Temporal variations in the incidence rate by subsite could suggest different carcinogenic pathways of right- and left-sided colon cancer. © 2013 Springer-Verlag Berlin Heidelberg.


Caldarella A.,Institute for Study and Cancer Prevention ISPO | Crocetti E.,Institute for Study and Cancer Prevention ISPO | Bianchi S.,University of Florence | Vezzosi V.,University of Florence | And 3 more authors.
Pathology and Oncology Research | Year: 2011

The aim of this study is to evaluate the prognostic values of some biological parameters in a population based series of female breast cancer patients. Through the Tuscan Cancer Registry all the invasive breast cancer cases diagnosed during the period 2004-2005 in the provinces of Florence and Prato, central Italy, were retrieved. Molecular subtypes were analyzed defined by immunohistochemical markers, by age, tumor size, lymph node status, histotype, grade of differentiation and proliferative marker. Out of 1487 patients 70.3% were luminal A subtype (ER/PR + HER2-), 15.6% luminal B (ER/PR + HER2+), 8.1% triple negative (ER/PR-HER2-), 6.0% HER2+ (ER/PR-HER2+); the 3 year survival rates were 93.3%, 89.5%, 86.3%, 82.7% respectively (p < 0.001). Analysis of survival by the Cox proportional hazards model showed an independent prognostic value of molecular classification. Our study revealed significant differences in clinicopathological characteristics among breast cancer molecular subtypes and confirmed their prognostic independent role. © 2011 Arányi Lajos Foundation.


Caldarella A.,Institute for Study and Cancer Prevention ISPO | Crocetti E.,Institute for Study and Cancer Prevention ISPO | Paci E.,Institute for Study and Cancer Prevention ISPO
Pathology and Oncology Research | Year: 2011

Neuroendocrine tumors are considered rare tumors: recently an increased incidence and an improvement in survival were described. We explore distribution, incidence and survival of neuroendocrine tumors using population based registry data. We extracted from the Tuscan Cancer Registry neuroendocrine tumors from 1985-2005, and we evaluated distribution, incidence ad survival according to sex, site of tumor, age and stage at diagnosis. 455 cases of neuroendocrine tumors were identified. The overall incidence increased over the study period from 0.7 per 100,000 per year to 1.6 among men (APC +3.6) and from 0.3 to 2.1 among women (APC +4.8). The anatomic distribution of tumors was lung 25.7%, small intestine 23.5%, appendix 10.9%, colon 10.3%, pancreas 9.4%, stomach 7.4%, and rectum 5.2%. Neuroendocrine tumors were more frequent among males and incidence rate increased with age. We observed increased incidence of neuroendocrine tumors, while survival did not change over time. Prognosis varied with age, stage and localization; females had better survival than males. The increase number of neuroendocrine tumors may be due, at least in part, to better registration and to improvement of diagnosis. © 2011 Arányi Lajos Foundation.


Caldarella A.,Institute for Study and Cancer Prevention ISPO | Crocetti E.,Institute for Study and Cancer Prevention ISPO | Paci E.,Institute for Study and Cancer Prevention ISPO
Journal of Neuro-Oncology | Year: 2011

Recently, an increasing incidence of brain tumors has been reported from multiple studies. Brain tumors diagnosed in the period 1985-2005 were identified through the Tuscan Cancer Registry, a population-based registry active since 1985 in the area of Florence and Prato. Age-standardized incidence rates and average annual percent change (APC) was calculated for the entire period from 1985 to 2005 for sex and behavior. A total of 4,417 brain tumors was registered, 1,900 (43%) in male and 2,517 (57%) in female patients. Malignant and benign tumor incidence rates were 8.3 and 4.1, respectively, among males and 6.4 and 7.2, respectively, among females. The age-adjusted annual incidence rate of all brain tumors was 13.9, with a statistically significant increasing rate throughout the period (APC: +3.2, CI 2.2-4.2). The annual incidence rate remained stable for malignant brain tumors but increased significantly for benign brain tumors (APC: +6.2, CI 4.5-7.9). In our population-based study, the incidence of brain tumors increased from 1985 to 2005 overall and for benign tumors, but not for malignant tumors. Part of the temporal variations may be attributed to improvement in diagnostic imaging techniques and, particularly for benign tumors, in changes in registration practice. © 2011 Springer Science+Business Media, LLC.


PubMed | Institute for Study and Cancer Prevention ISPO
Type: Journal Article | Journal: Journal of cancer research and clinical oncology | Year: 2013

In a population-based screening program, a percentage of tumors remain undetected; these tumors comprise a heterogeneous group, and they are more likely to have adverse prognostic features. The aim of this study was to identify differences in biological characteristics of screen-detected versus interval breast cancers in a population-based screening program according to molecular subtypes.We analyzed the population-based data from a long-running screening program in the area of Florence. Data on screening history and on age, T and N status, grade, histotype, hormonal status and Ki-67 and HER2 expression were retrieved. Subtypes of breast cancer were defined on the expression of ER, PR, Ki-67 and HER2: luminal A if ER/PR+, HER2- and Ki67 <14 %, luminal B (HER2 negative) if ER/PR+, HER2- and Ki67 14 %, luminal B (HER2 positive) if ER/PR+ and HER2+, triple negative if ER/PR-and HER2-, HER2 positive if ER/PR- and HER2+. Association between molecular subtypes and mode of detection will be evaluated by a logistic regression model adjusted for the potential confounding variables.Information about biomarkers was known for 277 cases, 211 screening-detected and 66 interval cancers. Among interval cases, the triple-negative cancers were more represented than luminal A (OR = 3.52; CI, 1.112-11.13; p = 0.0319), while the proportion of HER2+ was quite similar (OR = 1.57; p = 0.4709).Although made on a small number of cases, our results suggest a difference in distribution of molecular subtypes according to mode detection, confirming the results of earlier studies.

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